INHERITED DNA REPAIR AND CELL CYCLE GENE DEFECTS IN CHRONIC LYMPHOCYTIC LEUKEMIA
Author(s): ,
Nicholas S. Moore
Affiliations:
Dana-Farber Cancer Institute,Boston,United States;The Broad Institute of MIT and Harvard,Cambridge,United States
,
Saud H. Aldubayan
Affiliations:
Dana-Farber Cancer Institute,Boston,United States;The Broad Institute of MIT and Harvard,Cambridge,United States
,
Amaro Taylor-Weiner
Affiliations:
Dana-Farber Cancer Institute,Boston,United States;The Broad Institute of MIT and Harvard,Cambridge,United States
,
Stephan Stilgenbauer
Affiliations:
Department of Internal Medicine III,University of Ulm,Ulm,Germany
,
Gad Getz
Affiliations:
The Broad Institute of MIT and Harvard,Cambridge,United States
,
Catherine J. Wu
Affiliations:
Dana-Farber Cancer Institute,Boston,United States;The Broad Institute of MIT and Harvard,Cambridge,United States
,
Eliezer M. Van Allen
Affiliations:
Dana-Farber Cancer Institute,Boston,United States;The Broad Institute of MIT and Harvard,Cambridge,United States
Jennifer R. Brown
Affiliations:
Dana-Farber Cancer Institute,Boston,United States;The Broad Institute of MIT and Harvard,Cambridge,United States
EHA Library. Brown J. Jun 15, 2019; 266749; PS1132
Dr. Jennifer Brown
Dr. Jennifer Brown
Contributions
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Abstract

Abstract: PS1132

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
Chronic lymphocytic leukemia (CLL) is among the most heritable cancers, with 60% of disease risk genetically determined. However, most of the genetic heritability of CLL remains unexplained. Previously, we identified ATM as the first CLL risk gene.

Aims
Here we leverage a deep-learning-based germline variant calling algorithm to explore germline mutational enrichment in DNA repair and cell cycle genes in CLL.

Methods
A two-stage case-control analysis was conducted using gene-based mutational enrichment analysis of 50 established cancer predisposition DNA repair and cell cycle genes. In the discovery phase, a total of 285 Spanish patients and 5,608 ancestry-matched controls were evaluated. In the validation stage, an independent cohort of 514 European patients and 27,173 ancestry-matched controls were analyzed. An FDR correction was applied to both datasets and genes with a q-value < 0.2 in both cohorts were considered significant. 

Results
Our joint analysis of 799 CLL patients from 2 genetically distinct cohorts and 32,781 ancestry-matched cancer-free controls identified ATM and CHEK2 as significantly enriched in both CLL datasets. First, our analysis recaptured the previously reported finding of ATM variant enrichment in CLL patients. Carriers of pathogenic ATM mutations in our cohorts (n = 9 patients, discovery: 1.05%, validation: 1.17%) were 2.8–3.7 times more likely to develop CLL compared to cancer-free individuals (discovery: OR = 2.8, 95%CI = 0.7–9.0, q-value = 0.181; validation: OR = 3.7, 95%CI = 1.6–8.3, q-value = 0.0454). In addition, our analysis identified 21 CLL patients carrying pathogenic CHEK2 alterations (discovery: 1.40%, validation: 3.31%), making CLL patients 4.4-8.0 times more likely to carry such alterations compared to controls (discovery: OR = 8.0, 95%CI = 2.3–27.0, q-value = 0.026; validation: OR = 4.4, 95%CI = 2.5–7.3, q-value < 0.001). 

Conclusion
Our analysis of genetically distinct CLL cohorts, using a high-sensitivity variant calling algorithm, supports CHEK2 as a potentially novel CLL predisposition gene that may explain a portion of the missing monogenic heritability of CLL. In addition, this study highlights the DNA repair and cell cycle regulation pathways as potential drivers of CLL susceptibility.

Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research

Keyword(s): ATM, Cell cycle, Chronic lymphocytic leukemia, DNA repair

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